Synthetic silica fibers of different length, diameter and shape: synthesis and interaction with rat (NR8383) and human (THP-1) macrophages in vitro, including chemotaxis and gene expression profile.

BACKGROUND: Inhalation of biopersistent fibers like asbestos can cause strong chronic inflammatory effects, often resulting in fibrosis or even cancer. The interplay between fiber shape, fiber size and the resulting biological effects is still poorly understood due to the lack of reference materials. RESULTS: We investigated how length, diameter, aspect ratio, and shape of synthetic silica fibers influence inflammatory effects at doses up to 250 µg cm-2. Silica nanofibers were prepared with different diameter and shape. Straight (length ca. 6 to 8 µm, thickness ca. 0.25 to 0.35 µm, aspect ratio ca. 17:1 to 32:1) and curly fibers (length ca. 9 µm, thickness ca. 0.13 µm, radius of curvature ca. 0.5 µm, aspect ratio ca. 70:1) were dispersed in water with no apparent change in the fiber shape during up to 28 days. Upon immersion in aqueous saline (DPBS), the fibers released about 5 wt% silica after 7 days irrespectively of their shape. The uptake of the fibers by macrophages (human THP-1 and rat NR8383) was studied by scanning electron microscopy and confocal laser scanning microscopy. Some fibers were completely taken up whereas others were only partially internalized, leading to visual damage of the cell wall. The biological effects were assessed by determining cell toxicity, particle-induced chemotaxis, and the induction of gene expression of inflammatory mediators. CONCLUSIONS: Straight fibers were only slightly cytotoxic and caused weak cell migration, regardless of their thickness, while the curly fibers were more toxic and caused significantly stronger chemotaxis. Curly fibers also had the strongest effect on the expression of cytokines and chemokines. This may be due to the different aspect ratio or its twisted shape.

Iron nuclearity in mineral fibres: Unravelling the catalytic activity for predictive modelling of toxicity.

Chronic inflammation induced in vivo by mineral fibres, such as asbestos, is sustained by the cyclic formation of cytotoxic/genotoxic oxidant species that are catalysed by iron. High catalytic activity is observed when iron atoms are isolated in the crystal lattice (nuclearity=1), whereas the catalytic activity is expected to be reduced or null when iron forms clusters of higher nuclearity. This study presents a novel approach for systematically measuring iron nuclearity across a large range of iron-containing standards and mineral fibres of social and economic importance, and for quantitatively assessing the relation between nuclearity and toxicity. The multivariate curve resolution (MCR) empirical approach and density functional theory (DFT) calculations were applied to the analysis of UV-Vis spectra to obtain information on the nature of iron and nuclearity. This approach led to the determination of the nuclearity of selected mineral fibres which was subsequently used to calculate a toxicity-related index. High nuclearity-related toxicity was estimated for chrysotile samples, fibrous glaucophane, asbestos tremolite, and fibrous wollastonite. Intermediate values of toxicity, corresponding to a mean nuclearity of 2, were assigned to actinolite asbestos, amosite, and crocidolite. Finally, a low nuclearity-related toxicity parameter, corresponding to an iron-cluster with a lower catalytic power to produce oxidants, was assigned to asbestos anthophyllite.

Mechanisms of action of mineral fibres in a placental syncytiotrophoblast model: An in vitro toxicology study.

Asbestos has been widely used due to its unique characteristics. It is known that exposure to asbestos causes serious damage to health but one species, chrysolite, is still used because it is considered less toxic and not biopersistent in some countries. The aim of our study was to investigate if cellular process underlying the proliferation, differentiation and cell death of placental tissues could be modify in presence of asbestos fibres (50 µg/ml final concentration), long chrysolite fibres (CHR-L) and short chrysolite fibres (CHR-S), using BeWo cell line, an in vitro model that mimics the syncytiotrophoblast (STB), the outer layer of placental villi. Our data demonstrated that none of the fibres analysed alter syncytiotrophoblast formation but all of them induce ROS formation and reduced cell proliferation. Moreover, we showed that only CHR-L fibre induced was able to induce irreversible DNA alterations that carried cells to apoptosis. In fact, BeWo cells exposed to CHR-L fibre showed a significant increase in cleaved CASP3 protein, a marker of apoptosis. These data suggest that CHR-L may induce death of the placental villi leading to impaired placental development. The impairment of placental development is the basis of many gestational pathologies such as preeclampsia and intrauterine growth retardation. Since these pathologies are very dangerous for foetal and maternal life, we suggest to the gynaecologists to carefully evaluate the area of maternal residence, the working environment, the food used, and the materials used daily to avoid contact with these fibres as much as possible.

Toxicological and epidemiological approaches to carcinogenic potency modeling for mixed mineral fiber exposure: the case of fibrous balangeroite and chrysotile.

CONTEXT: Excess mesothelioma risk was observed among chrysotile miners and millers in Balangero, Italy. The mineral balangeroite has been identified in an asbestiform habit from the Balangero chrysotile mine (Italy). Previous studies did not contain a detailed description of the fiber dimensions, thus limiting possible approaches to estimating their carcinogenic potential. OBJECTIVES: To reconstruct excess mesothelioma risk based on characteristics of mixed fiber exposure. METHODS: The lengths and widths of particles from a sample of balangeroite were measured by transmission electron microscopy (TEM). Statistical analysis and modeling were applied to assess the toxicological potential of balangeroite. RESULTS: Balangeroite fibers are characterized as asbestiform, with geometric mean length of 10 µm, width of 0.54 µm, aspect ratio of 19, and specific surface area of 13.8 (1/µm). Proximity analysis shows dimensional characteristics of balangeroite close to asbestiform anthophyllite. Modeling estimates the average potency of balangeroite as 0.04% (95% CI 0.0058, 0.16) based on dimensional characteristics and 0.05% (95% CI-0.04, 0.24) based on epidemiological data. The available estimate of the fraction of balangeroite in the Balangero mine is very approximate. There were no data for airborne balangeroite fibers from the Balangero mine and no lung burden data are available. All estimates were performed using weight fractions of balangeroite and chrysotile. However, based on reasonable assumptions, of the seven cases of mesothelioma in the cohort, about three cases (43%) can be attributed to fibrous balangeroite. CONCLUSION: The presence of different types of mineral fibers in aerosolized materials even in small proportions can explain observed cancer risks.

Dimensions of elongate mineral particles and cancer: A review.

CONTEXT: Based on a decade-long exploration, dimensions of elongate mineral particles are implicated as a pivotal component of their carcinogenic potency. This paper summarizes current understanding of the discovered relationships and their importance to the protection of public health. OBJECTIVES: To demonstrate the relationships between cancer risk and dimensions (length, width, and other derivative characteristics) of mineral fibers by comparing the results and conclusions of previously published studies with newly published information. METHODS: A database including 59 datasets comprising 341,949 records were utilized to characterize dimensions of elongate particles. The descriptive statistics, correlation and regression analysis, combined with Monte Carlo simulation, were used to select dimensional characteristics most relevant for mesothelioma and lung cancer risk prediction. RESULTS: The highest correlation between mesothelioma potency factor and weight fraction of size categories is achieved for fibers with lengths >5.6 µm and widths ≤0.26 µm (R = 0.94, P < 0.02); no statistically significant potency was found for lengths <5 µm. These results are consistent with early published estimations, though are derived from a different approach. For combinations of amphiboles and chrysotile (with a consideration of a correction factor between mineral classes), the potency factors correlated most highly with a fraction of fibers longer than 5 µm and thinner than 0.2 µm for mesothelioma, and longer than 5 µm and thinner than 0.3 µm for lung cancer. Because the proportion of long, thin particles in asbestiform vs. non-asbestiform dusts is higher, the cancer potencies of the former are predicted at a significantly higher level. The analysis of particle dimensionality in human lung burden demonstrates positive selection for thinner fibers (especially for amosite and crocidolite) and prevailing fraction of asbestiform habit. CONCLUSION: Dimensions of mineral fibers can be confirmed as one of the main drivers of their carcinogenicity. The width of fibers emerges as a primary potency predictor, and fibers of all widths with lengths shorter than 5 µm seem to be non-impactful for cancer risk. The mineral dust with a fibrous component is primarily carcinogenic if it contains amphibole fibers longer than 5 µm and thinner than 0.25 µm.

Journey to the centre of the lung. The perspective of a mineralogist on the carcinogenic effects of mineral fibres in the lungs.

This work reviews the bio-chemical mechanisms leading to adverse effects produced when mineral fibres are inhaled and transported in the lungs from the perspective of a mineralogist. The behaviour of three known carcinogenic mineral fibres (crocidolite, chrysotile, and fibrous-asbestiform erionite) during their journey through the upper respiratory tract, the deep respiratory tract and the pleural cavity is discussed. These three fibres have been selected as they are the most socially and economically relevant mineral fibres representative of the classes of chain silicates (amphiboles), layer silicates (serpentine), and framework silicates (zeolites), respectively. Comparison of the behaviour of these fibres is made according to their specific crystal-chemical assemblages and properties. Known biological and subsequent pathologic effects which lead and contribute to carcinogenesis are critically reviewed under the mineralogical perspective and in relation to recent progress in this multidisciplinary field of research. Special attention is given to the understanding of the cause-effect relationships for lung cancer and malignant mesothelioma. Comparison with interstitial pulmonary fibrosis, or "asbestosis", will also be made here. This overview highlights open issues, data gaps, and conflicts in the literature for these topics, especially as regards relative potencies of the three mineral fibres under consideration for lung cancer and mesothelioma. Finally, an attempt is made to identify future research lines suitable for a general comprehensive model of the carcinogenicity of mineral fibres.

The Acute Toxicity of Mineral Fibres: A Systematic In Vitro Study Using Different THP-1 Macrophage Phenotypes.

Alveolar macrophages are the first line of defence against detrimental inhaled stimuli. To date, no comparative data have been obtained on the inflammatory response induced by different carcinogenic mineral fibres in the three main macrophage phenotypes: M0 (non-activated), M1 (pro-inflammatory) and M2 (alternatively activated). To gain new insights into the different toxicity mechanisms of carcinogenic mineral fibres, the acute effects of fibrous erionite, crocidolite and chrysotile in the three phenotypes obtained by THP-1 monocyte differentiation were investigated. The three mineral fibres apparently act by different toxicity mechanisms. Crocidolite seems to exert its toxic effects mostly as a result of its biodurability, ROS and cytokine production and DNA damage. Chrysotile, due to its low biodurability, displays toxic effects related to the release of toxic metals and the production of ROS and cytokines. Other mechanisms are involved in explaining the toxicity of biodurable fibrous erionite, which induces lower ROS and toxic metal release but exhibits a cation-exchange capacity able to alter the intracellular homeostasis of important cations. Concerning the differences among the three macrophage phenotypes, similar behaviour in the production of pro-inflammatory mediators was observed. The M2 phenotype, although known as a cell type recruited to mitigate the inflammatory state, in the case of asbestos fibres and erionite, serves to support the process by supplying pro-inflammatory mediators.

Fiber biodurability and biopersistence: historical toxicological perspective of synthetic vitreous fibers (SVFs), the long fiber paradigm, and implications for advanced materials.

Extensive toxicology studies of synthetic vitreous fibers (SVFs) demonstrated that fiber dimension, durability/dissolution, and biopersistence are critical factors for risk of fibrogenesis and carcinogenesis. Lessons learned from the SVF experience provide useful context for predicting hazards and risk of nano-enabled advanced materials. This review provides (1) a historical toxicological overview of animal and in vitro toxicology studies of SVFs, (2) key findings that long durable fibers pose a risk of fibrogenic and tumorigenic responses and not short fibers or long soluble fibers, (3) in vitro and in vivo test methods for biodurability and biopersistence and associated predictive thresholds for fibrosis or tumors, and (4) recommendations for testing of advanced materials. Generally, SVFs (fiber lengths >20 µm) with in vitro fiber dissolution rates greater than 100 ng/cm2/hr (glass fibers in pH 7 and stone fibers in pH 4.5) and in vivo fiber clearance less than WT1/2 40 or 50 days were not associated with fibrosis or tumors. Long biodurable and biopersistent fibers exceeding these fiber dissolution and clearance thresholds may pose a risk of fibrosis and cancer. Fiber length-, durability-, and biopersistent-dependent factors that influence pathogenicity of mineral fibers are also expected to affect the biological effects of high aspect ratio nanomaterials (HARN). Only with studies aimed to correlate in vitro durability, in vivo biopersistence, and biological outcomes will it be determined whether similar or different in vitro fiber dissolution and in vivo half-life thresholds, which exempt carcinogenicity classification of SVFs, can also apply to HARNs.

Acute cytotoxicity of mineral fibres observed by time-lapse video microscopy.

Inhalation of mineral fibres is associated with the onset of an inflammatory activity in the lungs and the pleura responsible for the development of fatal malignancies. It is known that cell damage is a necessary step for triggering the inflammatory response. However, the mechanisms by which mineral fibres exert cytotoxic activity are not fully understood. In this work, the kinetics of the early cytotoxicity mechanisms of three mineral fibres (i.e., chrysotile, crocidolite and fibrous erionite) classified as carcinogenic by the International Agency for Research on Cancer, was determined for the first time in a comparative manner using time-lapse video microscopy coupled with in vitro assays. All tests were performed using the THP-1 cell line, differentiated into M0 macrophages (M0-THP-1) and exposed for short times (8 h) to 25 µg/mL aliquots of chrysotile, crocidolite and fibrous erionite. The toxic action of fibrous erionite on M0-THP-1 cells is manifested since the early steps (2 h) of the experiment while the cytotoxicity of crocidolite and chrysotile gradually increases during the time span of the experiment. Chrysotile and crocidolite prompt cell death mainly via apoptosis, while erionite exposure is also probably associated to a necrotic-like effect. The potential mechanisms underlying these different toxicity behaviours are discussed in the light of the different morphological, and chemical-physical properties of the three fibres.

Rounded atelectasis after exposure to refractory ceramic fibres (RCF).

BACKGROUND: Refractory Ceramic fibres (RCF) are man-made mineral fibres used in high performance thermal insulation applications. Analogous to asbestos fibres, RCF are respirable, show a pleural drift and can persist in human lung tissue for more than 20 years after exposure. Pleural changes such as localised or diffuse pleural thickening as well as pleural calcification were reported. RESULT: A 45 years old man worked in high performance thermal insulation applications using refractory ceramic fibres (RCF) for almost 20 years. During a occupational medical prophylaxis to ensure early diagnosis of disorders caused by inhalation of aluminium silicate fibres with X-ray including high-resolution computed tomography (HRCT), bilateral pleural thickening was shown and a pleural calcification next to a rounded atelectasis was detected. Asbestos exposure could be excluded. In pulmonary function test a restrictive lung pattern could be revealed. In work samples scanning electron microscopy (SEM) including energy dispersive X-ray analysis (EDX) classified used fibres as aluminium silicate fibres. X-ray powder diffraction (XRD) and transmission electron microscopy (TEM) showed crystalline as well as amorphous fibres. CONCLUSIONS: A comprehensive lung function analysis and in case of restrictive lung disorders additional CT scans are needed in RCF exposed workers in accordance to the guidelines for medical occupational examinations comparable to asbestos exposed workers.

Asbestos: Mesothelioma / Mesotelioma

Since 2006, The Mesothelioma Center at Asbestos.com has been helping connect people impacted by mesothelioma and asbestos exposure with reliable information, world-class treatment. ----------------------------------------------------------- Desde 2006, o Mesothelioma Center em Asbestos.com tem ajudado a conectar as pessoas afetadas pelo mesotelioma e exposição ao amianto com informações confiáveis e tratamento.

A Critique of Helsinki Criteria for Using Lung Fiber Levels to Determine Causation in Mesothelioma Cases.

Asbestos is a known human carcinogen and the chief known cause of mesothelioma. In 1997, a group of experts developed the Helsinki Criteria, which established criteria for attribution of mesothelioma to asbestos. The criteria include two methods for causation attribution: 1) a history of significant occupational, domestic, or environmental exposure and/or 2) pathologic evidence of exposure to asbestos. In 2014, the Helsinki Criteria were updated, and these attribution criteria were not changed. However, since the Helsinki Criteria were first released in 1997, some pathologists, cell biologists, and others have claimed that a history of exposure cannot establish causation unless the lung asbestos fiber burden exceeds "the background range for the laboratory in question to attribute mesothelioma cases to exposure to asbestos." This practice ignores the impact on fiber burden of clearance/translocation over time, which in part is why the Helsinki Criteria concluded that a history of exposure to asbestos was independently sufficient to attribute causation to asbestos. After reviewing the Helsinki Criteria, we conclude that their methodology is fatally flawed because a quantitative assessment of a background lung tissue fiber level cannot be established. The flaws of the Helsinki Criteria are both technical and substantive. The 1995 paper that served as the scientific basis for establishing background levels used inconsistent methods to determine exposures in controls and cases. In addition, historic controls cannot be used to establish background fiber levels for current cases because ambient exposures to asbestos have decreased over time and control cases pre-date current cases by decades. The use of scanning electron microscope (SEM) compounded the non-compatibility problem; the applied SEM cannot distinguish talc from anthophyllite because it cannot perform selected area electron diffraction, which is a crucial identifier in ATEM for distinguishing the difference between serpentine asbestos, amphibole asbestos, and talc.

[Research progress of refractory ceramic fiber's damage to human respiratory system].

Refractory ceramic fibers (RCFs) , as the main substitute for asbestos, are widely used because of their high temperature resistance and good thermal insulation. In the air of its production and use places, RCFs are inhalable fibers that are easy to deposit in the lungs. The results of a number of epidemiological studies and a variety of toxicological methods have shown that RCFs are related to the occurrence of lung diseases. This article reviews the four aspects of RCFs-induced pleural thickening, pulmonary fibrosis, lung function damage, tumor and genetic damage, and looks forward to the prospects of RCFs on respiratory system damage related research.

Respiratory effects induced by occupational exposure to refractory ceramic fibers.

Refractory ceramic fibers (RCFs) are increasingly used as heating-insulated materials in various industries. However, toxicological and epidemiological studies focusing on the adverse effects of RCFs were still insufficient, particularly in China. We conducted a cross-sectional study to evaluate comprehensively the associations between occupational exposure to RCFs and respiratory health effects among Chinese workers. We measured and calculated cumulative RCFexposure levels of RCFs workers from the biggest RCFs factory in China. In total, 430 RCF-exposed workers and 121 controls were enrolled in this study. Physical examinations of the respiratory system were performed and serum levels of biomarkers including Clara cell protein 16 (CC16), surfactant protein D (SP-D), transforming growth factor ß1 (TGF-ß1), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined among all subjects. RCF exposure workers showed a higher prevalence rate of respiratory symptoms (cough: 11.9%) and lower levels of small airways function indices (V50 %: 82.71 ± 20.01, maximal mid expiratory flow (MMEF)%: 81.08 ± 19.56) compared with the control group (cough: 5.0%, V50 %: 90.64 ± 24.36, MMEF%: 88.83 ± 24.22). RCFs workers showed higher levels of TGF-ß1 (31.04 ng/mL) and 8-OHdG (130.72 ng/mL) and lower levels of CC16 (3.68 ng/mL) compared with the controls (TGF-ß1: 26.63 ng/mL, 8-OHdG: 106.86 ng/mL, CC16: 5.65 ng/mL). After adjusting for covariates, cumulative RCF exposure levels showed significant positive associations with the levels of TGF-ß1 and 8-OHdG and negative association with the level of CC16. Occupational RCF exposure could induce adverse respiratory health effects, including cough and small airways damage, which may correlate to the altered levels of lung damage markers (CC16 and TGF-ß1) and oxidative markers (8-OHdG).

Italian pool of asbestos workers cohorts: asbestos related mortality by industrial sector and cumulative exposure.

OBJECTIVE: Italy has been a large user of asbestos and asbestos containing materials until the 1992 ban. We present a pooled cohort study on long-term mortality in exposed workers. METHODS: Pool of 43 Italian asbestos cohorts (asbestos cement, rolling stock, shipbuilding, glasswork, harbors, insulation and other industries). SMRs were computed by industrial sector for the 1970-2010 period, for the major causes, using reference rates by age, sex, region and calendar period. RESULTS: The study included 51 801 subjects (5741 women): 55.9% alive, 42.6% died (cause known for 95%) and 1.5% lost to follow-up. Asbestos exposure was estimated at the plant and period levels. Asbestos related mortality was significantly increased. All industrial sectors showed increased mortality from pleural malignancies, and most also from peritoneal and lung cancer and asbestosis, with exposure related trend. Increased mortality was also observed for ovarian cancer and for bladder cancer. DISCUSSION: The study confirmed the increased risk for cancer of the lung, ovary, pleura and peritoneum but not of the larynx and the digestive tract. A large increase in mortality from asbestosis was observed.

Long-term instillation to four natural representative chrysotile of China induce the inactivation of P53 and P16 and the activation of C-JUN and C-FOS in the lung tissues of Wistar rats.

Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.

Characterization and assessment of the potential toxicity/pathogenicity of fibrous glaucophane.

In California, the metamorphic blueschist occurrences within the Franciscan Complex are commonly composed of glaucophane, which can be found with a fibrous habit. Fibrous glaucophane's potential toxicity/pathogenicity has never been determined and it has not been considered by the International Agency for Research on Cancer (IARC) as a potential carcinogen to date. Notwithstanding, outcrops hosting fibrous glaucophane are being excavated today in California for building/construction purposes (see for example the Calaveras Dam Replacement Project - CDRP). Dust generated by these excavation activities may expose workforces and the general population to this potential natural hazard. In this work, the potential toxicity/pathogenicity of fibrous glaucophane has been determined using the fibre potential toxicity index (FPTI). This model has been applied to a representative glaucophane-rich sample collected at San Anselmo, Marin County (CA, USA), characterized using a suite of experimental techniques to determine morphometric, crystal-chemical parameters, surface reactivity, biodurability and related parameters. With respect to the asbestos minerals, the FPTI of fibrous glaucophane is remarkably higher than that of chrysotile, and comparable to that of tremolite, thus supporting the application of the precautionary approach when excavating fibrous glaucophane-rich blueschist rocks. Because fibrous glaucophane can be considered a potential health hazard, just like amphibole asbestos, it should be taken into consideration in the standard procedures for the identification and assessment of minerals fibres in soil and air samples.

Empirical model of mesothelioma potency factors for different mineral fibers based on their chemical composition and dimensionality.

Context: The potency of various mineral fiber types to produce mesothelioma was previously evaluated for numerous cohorts, but the differences in potencies for distinct fiber types have yet to be explained. Objective: To develop an empirical model that would reconstruct mesothelioma potency factors for various types of fiber based on their chemical composition and dimensionality. Methods: Typical chemical composition and dimensionality metrics (aspect ratios) were obtained and combined with mesothelioma potency factors estimated by Hodgson and Darnton method for Quebec chrysotile, South Africa amosite, South Africa and Australian crocidolite, Russian anthophyllite, Libby amphiboles, and Turkey erionite. The forward stepwise log-log regression method was utilized to determine the best combination of input parameters. Results: Mesothelioma potency factors (RM) for selected cohorts were effectively reconstructed utilizing the median aspect ratio of fibers and equivalent fractions of SiO2, total Fe oxides or total equivalent Fe3+ as Fe2O3, and MgO. Modeled potency factors increase as the aspect ratio, SiO2, and total Fe oxide (or Fe2O3) content grow, and as the MgO content diminishes. Correlation coefficients up to 0.999, p < 0.01, were achieved. The models also yield reasonable estimates of mesothelioma potencies for other fiber types, including Bolivian crocidolite, Russian chrysotile, fluoro-edenite, and others. Conclusion: In spite of the empirical approach, the proposed models provide a starting point for targeted studies of mesothelioma mechanisms by elucidating significant contributing physicochemical factors. The models have an exploratory and preliminary character but can potentially be useful to introduce quantitative structure-activity relationship approaches for the toxicology of fibrous minerals.

Man-made mineral fiber effects on the expression of anti-oncogenes P53 and P16 and oncogenes C-JUN and C-FOS in the lung tissue of Wistar rats.

Man-made mineral fibers (MMMFs) are substitutes for asbestos. MMMFs are widely used as insulation, but their molecular mechanisms underlying the tumorigenic effects in vivo have been poorly studied. For this reason, this work aimed to explore the properties and carcinogenic molecular mechanisms of MMMFs. The three MMMFs, rock wool (RW), glass fibers (GFs), and ceramic fibers (CFs), were prepared into respirable dust. Particle size, morphology, and chemical composition were analyzed by laser particle analyzer, scanning electron microscope, and X-ray fluorescence spectrometer, respectively. The Wistar rats were administered multiple intratracheal instillations of three MMMFs once a month. Then, several parameters (e.g. body mass, lung mass, and lung histology) were measured at 1, 3, and 6 months. After that, levels of P53, P16, C-JUN, and C-FOS mRNA and protein were measured by quantitative real-time reverse transcription polymerase chain reaction and Western blotting. This work found that exposure to MMMFs could influence the growth of body mass and increase lung mass. General conditions showed white nodules and irregular atrophy. In addition, MMMFs could lead to inactivation of anti-oncogene P16 and activation of proto-oncogenes (C-JUN and C-FOS) in the mRNA and protein levels, in which GF and CF were more obvious compared with RW. The effect of MMMFs was different, which may be related to the physical and chemical characteristics of different MMMFs. In conclusion, MMMFs (GF and CF) could induce an unbalanced expression of cancer-related genes in the lung tissues of rats. The understanding of the determinants of toxicity and carcinogenicity provides a scientific basis for developing and introducing new safer MMMF products, and the present study provides some useful insights into the carcinogenic mechanism of MMMFs.

Particle toxicology and health - where are we?

BACKGROUND: Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global burden of disease, particles are also increasingly used for medical purposes. Over the past decades we have gained considerable experience in how particle properties and particle-bio interactions are linked to human health. This insight is useful for improved risk management in the case of unwanted health effects but also for developing novel medical therapies. The concepts that help us better understand particles' and fibres' risks include the fate of particles in the body; exposure, dosimetry and dose-metrics and the 5 Bs: bioavailability, biopersistence, bioprocessing, biomodification and bioclearance of (nano)particles. This includes the role of the biomolecule corona, immunity and systemic responses, non-specific effects in the lungs and other body parts, particle effects and the developing body, and the link from the natural environment to human health. The importance of these different concepts for the human health risk depends not only on the properties of the particles and fibres, but is also strongly influenced by production, use and disposal scenarios. CONCLUSIONS: Lessons learned from the past can prove helpful for the future of the field, notably for understanding novel particles and fibres and for defining appropriate risk management and governance approaches.